The genomics of the sniffles

Genome sequences of the cold virus could reveal new secrets behind its prowess.

Bang in the middle of sniffle season, researchers have released the full genome sequences of more than 100 strains of the
viruses responsible for most common colds.

The viruses all belong to the rhinovirus family, and have RNA genomes. Their sequences, published this week in Science1, could be used to design new therapies against colds or to determine, for example, why one strain can cause more severe symptoms
than another. "This is what rhinovirus researchers have been waiting for," says virologist Carita Savolainen-Kopra of the
National Institute for Health and Welfare in Helsinki, Finland.

Many consider a cold to be nothing more than a nuisance, but researchers have estimated that colds cost the United States
about $60 billion each year. And although adults may suffer merely a runny nose or scratchy throat, colds in children can
cause middle-ear infections or increase the likelihood of developing asthma. Asthma sufferers, in turn, can find that catching
a cold worsens their symptoms.

"From that perspective, rhinovirus deserves to be attacked with the modern tools we have available to us," says Stephen Liggett,
director of cardiopulmonary genomics at the University of Maryland Medical Center in Baltimore, and one of the authors of
the study.

What's more, a newly discovered class of rhinoviruses — called HRV-C — can cause serious, flu-like lung infections. "This
is not the common cold," says study author Ann Palmenberg, a virologist at the University of Wisconsin, Madison. "These viruses
are really nasty. These are like rhinoviruses on steroids."

Sniffle-omics

All this havoc is caused by a tiny virus only about 30 nanometres in diameter, with a genome that is a mere 7,000 bases long
— a minute speck compared with the human genome, which has more than three billion bases. Although the genomes of a few strains
of cold virus had been sequenced, no one had compiled the full sequences of the 99 strains frequently studied by researchers.
These have been collected from patients over decades and form a reference library.

Liggett, Palmenberg and their colleagues decided to fill this gap by sequencing the reference-library strains, along with
10 additional viruses isolated from patients with upper respiratory infections. They compared these sequences and the previously
reported HRV-C genomes with one another to look for patterns and evolutionary relationships (see human rhinovirus genome tree,
right).

The results suggest that three of the strains may comprise a further new rhinovirus species. The sequences also indicate that
when more than one strain infects a single cell, the viruses may exchange portions of their genomes — a phenomenon that, until
now, had not been described in rhinoviruses.

In addition, all of the strains have extremely variable RNA sequences in one specific region of the genome. In poliovirus,
this same region is important for virulence and the same could be true in the rhinoviruses, says Palmenberg.

Palmenberg also believes that the genome is structured to allow ribosomes, the molecular machines that read RNA and produce
a protein, to rapidly skip over regions of the genome that do not code for proteins. The mechanism may make the viruses more
competitive by allowing them to synthesize their proteins more quickly, but this hypothesis still needs to be tested in the
laboratory.

Next steps

With the sequences now in hand, researchers can begin to tackle these possibilities experimentally. Liggett says he and his
collaborators have moved on to sequence more strains, which were recently isolated from infected patients. With enough samples
like this, researchers may get a sense of which strains dominate in different regions of the world.

The data may also reveal the viral characteristics that are associated with longer, more symptomatic infections. "To date,
there has been a lack of understanding as to which rhinovirus gives you a more complex cold," says Liggett.

These additional clinical isolates would be useful, says Caroline Tapparel, a virologist at the University Hospital of Geneva
in Switzerland, but she cautions that with the exception of the troublesome HRV-C viruses, variable viral genome sequences
may not prove to be the primary determinant of virulence. "Ultimately, the immune status of the patient may have a greater
impact," she says.